ETS (E26) fusions have been proposed to constitute a unique molecular subtype of prostate cancer (PCA), as evidenced by both their mutual exclusivity with other proposed PCA subtypes and the fundamentally different chromatin biology conferred by ETS-positivity [1–6]. These findings have allowed the conception of a road map associating specific molecular subtypes of PCA with progression pathways, and pairing targeted therapies with particular PCA subtypes, similar to algorithms used in breast cancer and other haematological malignancies [1]. To date, however, the prognostic value of ETS gene rearrangements has remained uncertain and has generated conflicting results. The majority of published reports showing prognostic value have been documented on cohorts reflective of the natural history of PCA, while those not able to confirm any prognostic significance have been investigated in surgically treated cohorts, with few exceptions [7–20]. The vast majority of ETS gene rearrangements involve ERG, a prototypical ETS transcription factor that transcriptionally activates hundreds of genes.While not all of these rearrangments have prognostic value, several studies have characterized novel genes associated with ERG gene rearrangements and their respective signalling pathways [21–29]. Furthermore, other studies have chosen a differential expression approach between two groups of ERG-positive and -negative tumours to identify downstream deregulated genes and genes with biological significance in patient prognosis [30,31]. Taken together, these studies show that a thorough interrogation and characterization of the molecular mechanisms that result in, or result from, ERG-gene rearrangements will enable us to identify novel PCA biomarkers as well as characterize new pathways potentially involved in disease progression, allowing a better prediction of patient prognosis. It is also possible that a subset of these target genes could contribute to the ‘ERG-ness’ of a tumour, that is, a measure of the strength by which ERG-mediated regulation is active in the downstream gene pathway, independent of whether the tumour is ERG-positive or -negative; therefore, we hypothesized that ERG-ness, or an ERG-associated gene expression signature, would have more prognostic value and be more clinically relevant than ERG status itself. In the present study, we used a differential expression microarray approach, combined with a bioinformatics interrogation of ERG-negative and ERG-positive tumours using the singular value decomposition (SVD) method [32], to identify novel genes associated with disease progression and with prognostic implication for cancer recurrence and disease-specific mortality, regardless of ERG status. The SVD-based approaches discover genes that have high entropy on the whole expression data, unlike other methods that test single genes without considering the overall effect on the data. We further validate the prognostic significance of this signature across several cohorts of PCA patients.
